Esoma-DM1，一种基于Maytansinoid的疗法小分子药物结合物，用于神经内分泌肿瘤

背景：常规化疗的主要挑战在于它缺乏选择性和特异性，从而导致重大副作用。使用小分子药物缀合物（SMDC）通过将其耦合到靶向载体来确保细胞毒性药物的特定递送到肿瘤部位。这种有希望的策略可以通过选择特异性与生长抑素受体亚型2（SSTR2）的靶向载体来应用于神经内分泌肿瘤（NET）。另外，将双功能性螯合掺入分子中，可以使诊断和治疗放射性核素均匀。因此，它有助于监测SMDC在体内的分布，并允许实施组合疗法。在我们的研究中，我们设计了一种结合了SSTR2靶向的Octretate肽和细胞毒性剂DM1的SMDC，它通过螯合物桥接的接头（N3-PY-DOTAGA）。这种方法需要在相反的位置将靶向载体和药物结合起来，以避免不希望的空间阻碍效应。方法：DM1部分的合成（4）涉及三步合成途径，然后通过与无铜点击反应相结合。随后使用[111in]含有[111in]的标记具有很高的放射化学产量和纯度。在SSTR2转染的U2OS细胞中进行了疾病-DM1结合，摄取和内在化的体外评估。在H69-taumor轴承小鼠中进行了体内生物分布和荧光成像。结果：Esoma-DM1对SSTR2的IC50值类似于黄金标准DOTA-TATE。在U2OS.SSTR2细胞中[111in]内 - esoma-dm1的摄取比[111in] in-dota-tate低1.2倍。与[111in] In-dota-tate相比，[111in]内部 - ESOMA-DM1的H69- Xenograpted小鼠的肿瘤摄取更高。长时间的血液循环导致[111in] In- Esoma-DM1在高度血管化组织（例如肺，皮肤和心脏）中的积累增加。还观察到通过肾脏，肝脏和脾脏排泄。结论：Esoma-DM1是一种用于网络开发的SMDC，在体外显示出有希望的特征。但是，使用[111in] In-Esoma-DM1获得的体内结果表明需要进行调整以优化其分布。

Background: The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N3-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [111In]InCl3 gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eSOMA-DM1 exhibited an IC50 value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [111In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [111In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [111In]In-eSOMA-DM1 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. Conclusion: eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [111In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.